Purinergic Signalling

, Volume 11, Issue 3, pp 389–407 | Cite as

Selectivity is species-dependent: Characterization of standard agonists and antagonists at human, rat, and mouse adenosine receptors

  • Mohamad Wessam Alnouri
  • Stephan Jepards
  • Alessandro Casari
  • Anke C. Schiedel
  • Sonja Hinz
  • Christa E. MüllerEmail author
Original Article


Adenosine receptors (ARs) have emerged as new drug targets. The majority of data on affinity/potency and selectivity of AR ligands described in the literature has been obtained for the human species. However, preclinical studies are mostly performed in mouse or rat, and standard AR agonists and antagonists are frequently used for studies in rodents without knowing their selectivity in the investigated species. In the present study, we selected a set of frequently used standard AR ligands, 8 agonists and 16 antagonists, and investigated them in radioligand binding studies at all four AR subtypes, A1, A2A, A2B, and A3, of three species, human, rat, and mouse. Recommended, selective agonists include CCPA (for A1AR of rat and mouse), CGS-21680 (for A2A AR of rat), and Cl-IB-MECA (for A3AR of all three species). The functionally selective partial A2B agonist BAY60-6583 was found to additionally bind to A1 and A3AR and act as an antagonist at both receptor subtypes. The antagonists PSB-36 (A1), preladenant (A2A), and PSB-603 (A2B) displayed high selectivity in all three investigated species. MRS-1523 acts as a selective A3AR antagonist in human and rat, but is only moderately selective in mouse. The comprehensive data presented herein provide a solid basis for selecting suitable AR ligands for biological studies.


Agonist Antagonist Selectivity Species differences Potency 

Supplementary material

11302_2015_9460_MOESM1_ESM.pdf (180 kb)
ESM 1 (PDF 180 kb)


  1. 1.
    Burnstock G (2012) Purinergic signalling: Its unpopular beginning, its acceptance and its exciting future. Bioessays 34:218–225PubMedCrossRefGoogle Scholar
  2. 2.
    Burnstock G, Verkhratsky A (2009) Evolutionary origins of the purinergic signaling system. Acta Physiol (Oxf) 195:415–447CrossRefGoogle Scholar
  3. 3.
    Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J (2001) International union of pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53:527–552PubMedGoogle Scholar
  4. 4.
    Jacobson KA, Balasubramanian R, Deflorian F, Gao ZG (2012) G protein-coupled adenosine (P1) and P2Y receptors: ligand design and receptor interactions. Purinergic Signal 8:419–436PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Müller CE, Jacobson KJ (2011) Xanthines as adenosine receptor antagonists. Handb Exp Pharmacol 200:151–199PubMedCrossRefGoogle Scholar
  6. 6.
    Müller CE, Jacobson KA (2011) Recent developments in adenosine receptor ligands and their potential as novel drugs. Biochim Biophys Acta 1808:1290–1308PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Heisig F, Gollos S, Freudenthal SJ, El-Tayeb A, Iqbal J, Müller CE (2014) Synthesis of BODIPY derivatives substituted with various bioconjugatable linker groups: a construction kit for fluorescent labeling of receptor ligands. J Fluoresc 24:213–230PubMedCrossRefGoogle Scholar
  8. 8.
    Stoddart LA, Vernall AJ, Denman JL, Briddon SJ, Kellam B, Hill SJ (2012) Fragment screening at adenosine-A(3) receptors in living cells using a fluorescence-based binding assay. Chem Biol 19:1105–1115PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Kozma E, Jayasekara PS, Squarcialupi L, Paoletta S, Moro S, Federico S, Spalluto G, Jacobson KA (2013) Fluorescent ligands for adenosine receptors. Bioorg Med Chem Lett 23:26–36PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Xu F, Wu H, Katritch V, Han GW, Jacobson KA, Gao ZG, Cherezov V, Stevens RC (2011) Structure of an agonist-bound human A2A adenosine receptor. Science 332:322–327PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Jaakola VP, Griffith MT, Hanson MA, Cherezov V, Chien EY, Lane JR, Ijzerman AP, Stevens RC (2008) The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science 322:1211–1217PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Liu W, Chun E, Thompson AA, Chubukov P, Xu F, Katritch V, Han GW, Roth CB, Heitman LH, IJzerman AP, Cherezov V, Stevens RC (2012) Structural basis for allosteric regulation of GPCRs by sodium ions. Science 337:232–236PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Doré AS, Robertson N, Errey JC, Ng I, Hollenstein K, Tehan B, Hurrell E, Bennett K, Congreve M, Magnani F, Tate CG, Weir M, Marshall FH (2011) Structure of the adenosine A(2A) receptor in complex with ZM241385 and the xanthines XAC and caffeine. Structure 19:1283–1293PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    de Lera RM, Lim YH, Zheng J (2014) Adenosine A2A receptor as a drug discovery target. J Med Chem 57:3623–3650CrossRefGoogle Scholar
  15. 15.
    Chen JF, Eltzschig HK, Fredholm BB (2013) Adenosine receptors as drug targets-what are the challenges? Nat Rev Drug Discov 12:265–286PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Albrecht-Küpper BE, Leineweber K, Nell PG (2012) Partial adenosine A1 receptor agonists for cardiovascular therapies. Purinergic Signal 8:91–99PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Liao Y, Lin L, Lu D, Fu Y, Bin J, Xu D, Kitakaze M (2011) Activation of adenosine A1 receptor attenuates tumor necrosis factor-α induced hypertrophy of cardiomyocytes. Biomed Pharmacother 65:491–495PubMedCrossRefGoogle Scholar
  18. 18.
    Faulhaber-Walter R, Jou W, Mizel D, Li L, Zhang J, Kim SM, Huang Y, Chen M, Briggs JP, Gavrilova O, Schnermann JB (2011) Impaired glucose tolerance in the absence of adenosine A1 receptor signaling. Diabetes 60:2578–2587PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Teerlink JR, Iragui VJ, Mohr JP, Carson PE, Hauptman PJ, Lovett DH, Miller AB, Piña IL, Thomson S, Varosy PD, Zile MR, Cleland JG, Givertz MM, Metra M, Ponikowski P, Voors AA, Davison BA, Cotter G, Wolko D, Delucca P, Salerno CM, Mansoor GA, Dittrich H, O’Connor CM, Massie BM (2012) The safety of an adenosine A(1)-receptor antagonist, rolofylline, in patients with acute heart failure and renal impairment: findings from PROTECT. Drug Saf 35:233–244PubMedCrossRefGoogle Scholar
  20. 20.
    Nair PK, Marroquin OC, Mulukutla SR, Khandhar S, Gulati V, Schindler JT, Lee JS (2011) Clinical utility of regadenoson for assessing fractional flow reserve. JACC Cardiovasc Interv 4:1085–1092PubMedCrossRefGoogle Scholar
  21. 21.
    Cheng AS, Pegg TJ, Karamitsos TD, Searle N, Jerosch-Herold M, Choudhury RP, Banning AP, Neubauer S, Robson MD, Selvanayagam JB (2007) Cardiovascular magnetic resonance perfusion imaging at 3-tesla for the detection of coronary artery disease: a comparison with 1.5-tesla. J Am Coll Cardiol 49:2440–2449PubMedCrossRefGoogle Scholar
  22. 22.
    Lappas CM, Rieger JM, Linden J (2005) A2A adenosine receptor induction inhibits IFN-gamma production in murine CD4+ T cells. J Immunol 174:1073–1080PubMedCrossRefGoogle Scholar
  23. 23.
    Haskó G, Kuhel DG, Chen JF, Schwarzschild MA, Deitch EA, Mabley JG, Marton A, Szabó C (2000) Adenosine inhibits IL-12 and TNF-[alpha] production via adenosine A2A receptor-dependent and independent mechanisms. FASEB J 14:2065–2074PubMedCrossRefGoogle Scholar
  24. 24.
    Flögel U, Burghoff S, van Lent PL, Temme S, Galbarz L, Ding Z, El-Tayeb A, Huels S, Bönner F, Borg N, Jacoby C, Müller CE, van den Berg WB, Schrader J (2012) Selective activation of adenosine A2A receptors on immune cells by a CD73-dependent prodrug suppresses joint inflammation in experimental rheumatoid arthritis. Sci Transl Med 4:146ra108PubMedGoogle Scholar
  25. 25.
    Armentero MT, Pinna A, Ferré S, Lanciego JL, Müller CE, Franco R (2011) Past, present and future of A(2A) adenosine receptor antagonists in the therapy of Parkinson’s disease. Pharmacol Ther 132:280–299PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Salamone JD, Collins-Praino LE, Pardo M, Podurgiel SJ, Baqi Y, Müller CE, Schwarzschild MA, Correa M (2013) Conditional neural knockout of the adenosine A(2A) receptor and pharmacological A(2A) antagonism reduce pilocarpine-induced tremulous jaw movements: studies with a mouse model of parkinsonian tremor. Eur Neuropsychopharmacol 23:972–977PubMedCrossRefGoogle Scholar
  27. 27.
    Jerónimo-Santos A, Batalha VL, Müller CE, Baqi Y, Sebastião AM, Lopes LV, Diógenes MJ (2014) Impact of in vivo chronic blockade of adenosine A2A receptors on the BDNF-mediated facilitation of LTP. Neuropharmacology 83:99–106PubMedCrossRefGoogle Scholar
  28. 28.
    Jenner P (2005) Istradefylline, a novel adenosine A2A receptor antagonist, for the treatment of Parkinson’s disease. Expert Opin Investig Drugs 14:729–738PubMedCrossRefGoogle Scholar
  29. 29.
    Dungo R, Deeks ED (2013) Istradefylline: first global approval. Drugs 73:875–882PubMedCrossRefGoogle Scholar
  30. 30.
    Koupenova M, Johnston-Cox H, Vezeridis A, Gavras H, Yang D, Zannis V, Ravid K (2012) A2B adenosine receptor regulates hyperlipidemia and atherosclerosis. Circulation 125:354–363PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Michael S, Warstat C, Michel F, Yan L, Müller CE, Nieber K (2010) Adenosine A(2A) agonist and A(2B) antagonist mediate an inhibition of inflammation-induced contractile disturbance of a rat gastrointestinal preparation. Purinergic Signal 6:117–124PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Figler RA et al (2011) Links between insulin resistance, adenosine receptors and inflammatory markers in mice and humans. Diabetes 60:669–679PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Haskó G, Csóka B, Németh ZH, Vizi ES, Pacher P (2009) A2B adenosine receptors in immunity and inflammation. Trends Immunol 30:263–270PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Xiang HJ, Chai FL, Wang DS, Dou KF (2011) Downregulation of the adenosine a2b receptor by RNA interference inhibits hepatocellular carcinoma cell growth. ISNR Oncol 2011:875684–875687Google Scholar
  35. 35.
    Cekic C, Sag D, Li Y, Theodorescu D, Strieter RM, Linden J (2012) Adenosine A2B receptor blockade slows growth of baldder and breast tumors. J Immunol 188:198–205PubMedCrossRefGoogle Scholar
  36. 36.
    Silverman MH, Strand V, Markovits D, Nahir M, Reitblat T, Molad Y, RosnerI RM, Mader R, Adawi M, Caspi D, Tishler M, Langevitz P, Rubinow A, Friedman J, Green L, Tanay A, Ochaion A, Cohen S, Kerns WD, Cohn I, Fishman-Furman S, Farbstein M, Yehuda SB, Fishman P (2008) Clinical evidence for the utilization of A3 adenosine receptor as a target to treat rheumatoid arthritis: data from phase II clinical trial. J Rheumatol 35:41–48PubMedGoogle Scholar
  37. 37.
    Koscsó B, Csóka B, Pacher P, Haskó G (2011) Investigational A3 adenosine receptor targeting agents. Expert Opin Investig Drugs 20:757–768PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Wang Z, Do CW, Avila MY, Peterson-Yantorno K, Stone RA, Gao ZG, Joshi B, Besada P, Jeong LS, Jacobson KA, Civan MM (2010) Nucleosine-derived antagonists to A3 adenosine receptors lower mouse intraocular pressure and act across species. Exp Eye Res 90:146–154PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Müller CE, Scior T (1993) Adenosine receptors and their modulators. Pharm Acta Helv 68:77–111PubMedCrossRefGoogle Scholar
  40. 40.
    Auchampach JA, Kreckler LM, Wan TC, Maas JE, van der Hoeven D, Gizewski E, Narayanan J, Maas GE (2009) Characterization of the A2Badenosinereceptor from mouse, rabbit, and dog. J Pharmacol Exp Ther 329:2–13PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Müller CE, Stein B (1996) Adenosine receptor antagonists: Structure and potential therapeutic applications. Curr Pharmaceut Design 2:501–530Google Scholar
  42. 42.
    X-d J, von Lubitz D, Olah ME, Stiles GL, Jacobson KA (1994) Species differences in ligands affinity at central A3 adenosine receptors. Drug Develop Res 33:51–59CrossRefGoogle Scholar
  43. 43.
    Weyler S, Fülle F, Diekmann M, Schumacher B, Hinz S, Klotz KN, Müller CE (2006) Improving potency, selectivity, and water solubility of adenosine A1 receptor antagonists: xanthines modified at position 3 and related pyrimido[1,2,3-cd] purinediones. Chem Med Chem 1:891–902PubMedCrossRefGoogle Scholar
  44. 44.
    Yan L, Bertarelli DC, Hayallah AM, Meyer H, Klotz KN, Müller CE (2006) A new synthesis of sulfonamides by aminolysis of p-nitrophenylsulfonates yielding potent and selective adenosine A2B receptor antagonists. J Med Chem 49:4384–4391PubMedCrossRefGoogle Scholar
  45. 45.
    Müller CE, Shi D, Manning M Jr, Daly JW (1993) Synthesis of paraxanthine analogs (1,7-disubstituted xanthines) and other xanthinesunsubstituted at the 3-position: structure-activity relationships at adenosine receptors. J Med Chem 36:3341–3349PubMedCrossRefGoogle Scholar
  46. 46.
    Borrmann T, Hinz S, Bertarelli DC, Li W, Florin NC, Scheiff AB, Müller CE (2009) 1-alkyl-8-(piperazine-1-sulfonyl) phenylxanthines: development and characterization of adenosineA2B receptor antagonists and a new radioligand with subnanomolar affinity and subtype specificity. J Med Chem 52:3994–400PubMedCrossRefGoogle Scholar
  47. 47.
    Hockemeyer J, Burbiel JC, Müller CE (2004) Multigram-scale syntheses, stability, and photoreactions of A2A adenosine receptor antagonists with 8-styrylxanthine structure: Potential drugs for Parkinson’s disease. J Org Chem 69:3308–3318PubMedCrossRefGoogle Scholar
  48. 48.
    Neustadt BR, Hao J, Lindo N, Greenlee WJ, Stamford AW, Tulshian D, Ongini E, Hunter J, Monopoli A, Bertorelli R, Foster C, Arik L, Lachowicz J, Ng K, Feng KI (2007) Potent, selective, and orally active adenosine A2A receptor antagonists: Arylpiperazine derivatives of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c] pyrimidines. Bioorg Med Chem Lett 5:1376–1380CrossRefGoogle Scholar
  49. 49.
    Klotz KN, Hessling J, Hegler J, Owman C, Kull B, Fredholm BB, Lohse MJ (1998) Comparative pharmacology of human adenosine receptor subtypes—Characterization of stably transfected receptors in CHO cells. Naunyn Schmiedebergs Arch Pharmacol 357:1–9PubMedCrossRefGoogle Scholar
  50. 50.
    Klotz KN, Lohse MJ, Schwabe U, Cristalli G, Vittori S, Grifantini M (1989) 2-Chloro-N6-[3H] cyclopentyladenosine ([3H]CCPA)- a high affinity agonist radioligand for A1 adenosine receptors. Naunyn Schmiedebergs Arch Pharmacol 340:679–683PubMedCrossRefGoogle Scholar
  51. 51.
    Schumacher B (2002) Identifizierung, Struktur-Wirkungsbeziehungen und Aktivitätsprofile neuer Adenosinrezeptor-Liganden, University of BonnGoogle Scholar
  52. 52.
    Reith U (2001) Native und rekombinante humane Adenosinrezeptoren: Charakterizierung, Interaktion mit pflanzlichen Inhaltsstoffen und Suche nach neuen Leitstrukturen, University of BonnGoogle Scholar
  53. 53.
    Sihver W, Schulze A, Wutz W, Stüsgen S, Olsson RA, Bier D, Holschbach MH (2009) Autoradiographiccomparison of in vitro binding characteristics of various tritiated adenosine A2A receptor ligands in rat, mouse and pig brain and first ex vivo results. Eur J Pharmacol 616:107–114PubMedCrossRefGoogle Scholar
  54. 54.
    Daly JW, Padgett WL, Secunda SI, Thompson RD, Olsson RA (1993) Structure-activity relationships for 2-substituted adenosines at A1 and A2 adenosine receptors. Pharmacology 46:91–100PubMedCrossRefGoogle Scholar
  55. 55.
    Vittori S, Lorenzen A, Stannek C, Costanzi S, Volpini R, IJzerman AP, Kunzel JK, Cristalli G (2000) N-cycloalkyl derivatives of adenosine and 1-deazaadenosine as agonists and partial agonists of the A(1) adenosine receptor. J Med Chem 43:250–260PubMedCrossRefGoogle Scholar
  56. 56.
    Fredholm BB, IJzerman AP, Jacobson KA, Linden J, Müller CE (2011) International union of basic and clinical pharmacology. LXXXI. Nomenclature and classification of adenosine receptors-an update. Pharmacol Rev 63:1–34PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Tchilibon S, Joshi BV, Kim SK, Duong HT, Gao ZG, Jacobson KA (2005) (N)-methanocarba 2,N6-disubstituted adenine nucleosides as highly potent and selective A3 adenosine receptor agonists. J Med Chem 6:1745–1758CrossRefGoogle Scholar
  58. 58.
    Müller CE (2001) adenosine receptor ligands-recent developments part I. Agonists. Curr Med Chem 7:1269–1288CrossRefGoogle Scholar
  59. 59.
    Jacobson KA (1998) Adenosine A3 receptors: Novel ligands and paradoxical effects. Trends Pharmacol Sci 5:184–191CrossRefGoogle Scholar
  60. 60.
    Abo-Salem OM, Hayallah AM, Bilkei-Gorzo A, Filipek B, Zimmer A, Müller CE (2004) Antinociceptive effects of novel A2B adenosine receptor antagonists. J Pharmacol Exp Ther 1:358–366Google Scholar
  61. 61.
    Kenneth AK, Ijzerman AP, Linden J (1999) 1,3-dialkylxanthine derivatives having high potency as antagonists at human A2B adenosine receptors. Drug Devel Res 47:45–53CrossRefGoogle Scholar
  62. 62.
    Grahner B, Winiwarter S, Lanzner W, Müller CE (1994) Synthesis and structure-activity relationships of deazaxanthines: Analogs of potent A1- and A2-adenosine receptor antagonists. J Med Chem 37:1526–1534PubMedCrossRefGoogle Scholar
  63. 63.
    Bulicz J, Bertarelli DC, Baumert D, Fülle F, Müller CE, Heber D (2006) Synthesis and pharmacology of pyrido [2,3-d] pyrimidinediones bearing polar substituents as adenosine receptor antagonists. Bioorg Med Chem 14:2837–2849PubMedCrossRefGoogle Scholar
  64. 64.
    Massip S, Guillon J, Bertarelli D, Bosc JJ, Léger JM, Lacher S, Bontemps C, Dupont T, Müller CE, Jarry C (2006) Synthesis and preliminary evaluation of new 1- and 3-[1-(2-hydroxy-3-phenoxypropyl)] xanthines from 2-amino-2-oxazolines as potential A1 and A2A adenosine receptor antagonists. Bioorg Med Chem 14:2697–2719PubMedCrossRefGoogle Scholar
  65. 65.
    Klotz KN, Vogt H, Tawfik-Schlieper H (1991) Comparison of A1 adenosine receptors in brain from different species by radioligand binding and photoaffinity labelling. Naunyn Schmiedebergs Arch Pharmacol 343:196–201PubMedCrossRefGoogle Scholar
  66. 66.
    Kieć-Kononowicz K, Drabczyńska A, Pękala E, Michalak B, Müller CE, Schumacher B, Karolak-Wojciechowska J, Duddeck H, Rockitt S, Wartchow R (2001) New developments in A1 and A2A adenosine receptor antagonists. Pure Appl Chem 73:1411–1420Google Scholar
  67. 67.
    Kim YC, Ji X, Melman N, Linden J, Jacobson KA (2000) Anilide derivatives of an 8-phenylxanthine carboxylic congener are highly potent and selective antagonists at human A(2B) adenosine receptors. J Med Chem 43:1165–1172PubMedCrossRefGoogle Scholar
  68. 68.
    Akkari R, Burbiel JC, Hockemeyer J, Müller CE (2006) Recent progress in the development of adenosine receptor ligands as antiinflammartory drugs. Curr Top Med Chem 6:1375–1379PubMedCrossRefGoogle Scholar
  69. 69.
    Gao ZG, Blaustein JB, Gross AS, Melman N, Jacobson KA (2003) N6-Substituted adenosine derivatives: selectivity, efficacy, and species differences at A3 adenosine receptors. Biochem Pharmacol 65:1675–1684PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Müller CE (2001) A3 adenosine receptor antagonsits. Mini Rev Med Chem 1:417–427PubMedCrossRefGoogle Scholar
  71. 71.
    Olson KR, Eglen RM (2007) Beta-galactosidase complementation: a cell-based luminescent assay platform for drug discovery. Assay Drug Dev Technol 5:137–144PubMedCrossRefGoogle Scholar
  72. 72.
    Müller CE, Maurinsh J, Sauer R (2000) Binding of [3H]MSX-2 (3-(3-hydroxypropyl)-7-methyl-8-(m-methoxystyryl)-1-propargylxanthine) to rat striatal membranes—a new, selective antagonist radioligand for A(2A) adenosine receptors. Eur J Pharm Sci 10:259–265PubMedCrossRefGoogle Scholar
  73. 73.
    Bertarelli DC, Diekmann M, Hayallah AM, Rüsing D, Iqbal J, Preiss B, Verspohl EJ, Müller CE (2006) Characterization of human and rodent native and recombinant adenosine A(2B) receptors by radioligand binding studies. Purinergic Signal 2:559–571PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Seibt BF, Schiedel AC, Thimm D, Hinz S, Sherbiny FF, Müller CE (2013) The second extracellular loop of GPCRs determines subtype-selectivity and controls efficacy as evidenced by loop exchange study at A2 adenosine receptors. Biochem Pharmacol 85:1317–1329PubMedCrossRefGoogle Scholar
  75. 75.
    Kim SA, Marshall MA, Melman N, Kim HS, Müller CE, Linden J, Jacobson KA (2002) Structure-activity relationships at human and rat A2B adenosine receptors of xanthine derivatives substituted at the 1-, 3-, 7-, and 8-positions. J Med Chem 45:2131–2138PubMedCrossRefGoogle Scholar
  76. 76.
    Bruns RF, Lu GH, Pugsley TA (1986) Characterization of the A2 adenosine receptor labeled by [3H]NECA in rat striatal membranes. Mol Pharmacol 29:331–346PubMedGoogle Scholar
  77. 77.
    Hayallah AM, Sandoval-Ramírez J, Reith U, Schobert U, Preiss B, Schumacher B, Daly JW, Müller CE (2002) 1,8-disubstituted xanthine derivatives: Synthesis of potent A2B-selective adenosine receptor antagonists. J Med Chem 45:1500–1510PubMedCrossRefGoogle Scholar
  78. 78.
    Müller CE, Diekmann M, Thorand M, Ozola V (2002) [(3)H]8-Ethyl-4-methyl-2-phenyl-(8R)-4,5,7,8-tetrahydro-1H-imidazo [2,1-i]-purin-5-one ([(3)H]PSB-11), a novel high-affinity antagonist radioligand for human A(3) adenosine receptors. Bioorg Med Chem Lett 12:501–503PubMedCrossRefGoogle Scholar
  79. 79.
    Salvatore CA, Jacobson MA, Taylor HE, Linden J, Johnson RG (1993) Molecular cloning and characterization of the human A3 adenosine receptor. Proc Natl Acad Sci U S A 90:10365–10369PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    van Galen PJ, van Bergen AH, Gallo-Rodriguez C, Melman N, Olah ME, IJzerman AP, Stiles GL, Jacobson KA (1994) A binding site model and structure-activity relationships for the rat A3 adenosine receptor. Mol Pharmacol 45:1101–1111PubMedGoogle Scholar
  81. 81.
    Rosentreter U, Henning R, Bauser M, Krämer T, Vaupel A, Hübsch W, Dembowsky K, Salcher-Schraufstätter O, Stasch J P, Krahn T, Perzborn E (2006) Substituted 2-thio-3,5-dicyano-4-aryl-6-aminopyridines and the use thereof. 1–273Google Scholar
  82. 82.
    van der Hoeven D, Wan TC, Gizewski ET, Kreckler LM, Maas JE, Van Orman J, Ravid K, Auchampach JA (2011) A role for the low-affinity A2B adenosine receptor in regulating superoxide generation by murine neutrophils. J Pharmacol Exp Ther 338:1004–1012PubMedCentralPubMedCrossRefGoogle Scholar
  83. 83.
    Hinz S, Lacher SK, Seibt BF, Müller CE (2014) BAY60-6583 acts as a partial agonist at adenosine A2B receptors. J Pharmacol Exp Ther 349:427–436PubMedCrossRefGoogle Scholar
  84. 84.
    Jacobson KA (2013) Structure-based approaches to ligands for G-protein-coupled adenosine and P2Y receptors, from small molecules to nanoconjugates. J Med Chem 56:3749–3767PubMedCentralPubMedCrossRefGoogle Scholar
  85. 85.
    Murphree LJ, Marshall MA, Rieger JM, MacDonald TL, Linden J (2002) Human A(2A) adenosine receptors: High-affinity agonist binding to receptor-G protein complexes containing Gbeta(4). Mol Pharmacol 61:455–462PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  • Mohamad Wessam Alnouri
    • 1
  • Stephan Jepards
    • 1
  • Alessandro Casari
    • 1
  • Anke C. Schiedel
    • 1
  • Sonja Hinz
    • 1
  • Christa E. Müller
    • 1
    Email author
  1. 1.Pharma Center Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry IUniversity of BonnBonnGermany

Personalised recommendations